Tazpen

Tazpen

piperacillin + tazobactam

Manufacturer:

Mylan Lab

Distributor:

Unimed
Full Prescribing Info
Contents
Piperacillin, tazobactam.
Description
Each 4.5 g vial contains: Sterile mixture of Piperacillin sodium and Tazobactam sodium equivalent to Piperacillin 4.0 g and Tazobactam 0.50 g. It contains no excipients or preservatives.
White to off-white sterile, lyophilised powder of piperacillin and tazobactam as the sodium salts filled into glass vials. After reconstitution, the solution should be clear, colourless to pale yellow, free from visible particles.
Action
Pharmacology: Piperacillin, a broad spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulfone, is a potent inhibitor of many β-lactamases, including the plasmid and chromosomally mediated enzymes that commonly cause resistance to penicillins. The presence of tazobactam in the TAZPEN formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it. Thus, TAZPEN combines the properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
Pharmacokinetics: Absorption: Peak plasma concentrations of piperacillin sodium and tazobactam sodium are attained immediately after completion of an intravenous infusion.
Distribution: Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid and bile. Both piperacillin and tazobactam are approximately 30% bound to plasma proteins in adults.
Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in adult subjects with non-inflamed meninges, as with other penicillins.
Both Piperacillin and Tazobactam cross the placenta. Piperacillin is distributed into milk. It is not known whether tazobactam is distributed into milk.
Elimination: Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug.
In adults, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours.
Impaired liver function: The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects.
Impaired renal function: The half-lives of piperacillin and of tazobactam increase with decreasing creatinine clearance. In adults with creatinine clearance below 20 mL/min, the increase in half-life is two-fold for piperacillin and four-fold for tazobactam compared to subjects with normal renal function.
Children: Piperacillin and tazobactam pharmacokinetics were studied in paediatric patients 2-9 months of age. The clearance of both compounds is slower in the younger patients compared to older children and adults.
Microbiology: Piperacillin and Tazobactam is active against most strains of the following β-lactamase producing and non β-lactamase producing microorganisms: Gram-negative bacteria: Escherichia coli, Citrobacter sp., Enterobacter sp. (including E. cloacae), Serratia sp. (including S. marcescens), Pseudomonas aeruginosa and other Pseudomonas sp., Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis, Acinetobacter sp., Haemophilus influenza, Shigella sp., Campylobacter sp.
Gram-positive bacteria: Streptococci (S. pneumoniae, S. pyogenes, S. agalactiae, S. viridans), Enterococci (E. faecalis), Staphylococcus aureus (not methicillin-resistant S. aureus), S. epidermidis (coagulase-negative staphylococci).
Anaerobic bacteria: Bacteroides spp. including Bacteroides fragilis group, Peptostreptococcus spp., Fusobacterium spp., Eubacterium group, Clostridia spp., Veillonella spp.
Indications/Uses
TAZPEN is indicated for the treatment of systemic and/or local bacterial infections caused by susceptible organisms (detected/suspected) in the conditions listed as follows: Lower respiratory tract infections; Urinary tract infections (complicated and uncomplicated); Intra-abdominal infections; Skin and skin structure infections; Bacterial septicaemia; Polymicrobic infections including those where aerobic and anaerobic organisms are suspected (intra-abdominal, skin and skin structure, lower respiratory tract); Bacteria infections in neutropenic adults or children (in combination with an aminoglycoside).
Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial susceptibility testing are known.
Dosage/Direction for Use
Dosage: Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.
Adults and children 12 years and older with Normal Renal Function: Usual dose: 4.5 g given every eight hours. The total daily dose depends on the severity and localization of the infection and can vary from 2.25 g to 4.5 g administered every six or eight hours.
Neutropenia: Recommended dose: 4.5 g given every six hours in combination with an aminoglycoside.
Children under the age of 12 years: Recommended only for the treatment of children with neutropenia. TAZPEN should not be used in children who do not have neutropenia.
Children weighing more than 50 kg: Follow adult dosing guidance, including the aminoglycoside.
Children with Normal Renal Function and weighing less than 50 kg: Adjust dose to 90 mg/kg (80 mg piperacillin/10 mg tazobactam) given every 6 hours in combination with an aminoglycoside.
Hospitalized children with intra-abdominal infection: For children aged 2 to 12 years, weighing up to 40kg, and with normal renal function, the recommended dosage is 112.5 mg/kg (100 mg piperacillin/12.5 mg tazobactam) every 8 hours.
For children aged 2 to 12 years, weighing over 40 kg, and normal renal function, follow the adult dose guidance, i.e. 4.5 g (4 g piperacillin/0.5 g tazobactam) every 8 hours. The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.
Elderly: Recommended dose the same as adults except in cases of renal impairment.
Renal insufficiency: Adults and Children weighing more than 50 kg: The intravenous dose should be adjusted to the degree of actual renal function impairment. The suggested daily doses are as follows in Table 1: See Table 1.

Click on icon to see table/diagram/image

For patients on haemodialysis, the maximum daily dose is 8 g/1 g/day Piperacillin and Tazobactam. In addition, because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2 g piperacillin/0.25 g tazobactam should be administered following each dialysis period. For patients with renal failure and hepatic insufficiency, measurement of serum levels of TAZPEN will provide additional guidance for adjusting dosage.
Children weighing less than 50 kg: The intravenous dosage should be adjusted to the degree of actual renal impairment as in Table 2: See Table 2.

Click on icon to see table/diagram/image

Children weighing less than 50 kg on haemodialysis: Recommended dose is 45 mg/kg every 8 hours. The pharmacokinetics of piperacillin and tazobactam have not been studied in paediatric patients with renal impairment. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval dose should be adjusted accordingly. In patients with renal insufficiency or hemodialysis patients, intravenous dosages and administration intervals should be adjusted to the degree of renal function impairment.
Duration of therapy: Therapy is recommended to be a minimum of 5 days and maximum of 14 days, considering that dose administration should continue at least 48 hours after the resolution of clinical signs and symptoms or fever.
Administration: TAZPEN may be given by slow intravenous injection (3-5 minutes) or by infusion (20-30 minutes).
Directions for Reconstitution and Dilution: Diluents for reconstitution: Sterile water for injection; Sodium chloride injection; Bacteriostatic Water/Benzyl Alcohol; Bacteriostatic Saline/Benzyl Alcohol; Bacteriostatic Water/Parabens; Bacteriostatic Saline/Parabens.
IV injection: Reconstitute each vial with the volume of diluent shown in the table as follows, using one of the previously mentioned diluents. Shake until dissolved. (See Table 3.)

Click on icon to see table/diagram/image

IV infusion: Reconstitute each vial with at least 20 mL using one of the reconstitution diluents previously mentioned. Shake until dissolved. The reconstituted solution may be further diluted (recommended volume per dose of 50-150 mL) with a compatible IV solution listed as follows: 0.9% Sodium Chloride for Injection; Sterile Water for Injection*; Dextrose 5%; Dextran 6% in Saline.
Administer by infusion over a period of at least 30 min. During the infusion, it is desirable to discontinue the primary infusion solution.
Note:* Maximum recommended volume per dose of Sterile Water for Injection is 50 mL.
Overdosage
There have been post-marketing reports of overdose with piperacillin and tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhea have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either piperacillin-tazobactam may be reduced by haemodialysis. In case of severe, anaphylactic reactions, the usual counter measures are to be initiated.
Contraindications
The use of TAZPEN is contraindicated in patients with a history of allergic reactions to any of the penicillins and/or cephalosporins or β-lactamase inhibitors.
Warnings
Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with penicillins including piperacillin and tazobactam for injection. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with TAZPEN for injection, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, TAZPEN should be discontinued and appropriate therapy instituted. Serious anaphylactic/anaphylactoid reactions (including shock) require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated.
Antibiotic-associated pseudomembranous colitis has been reported with many antibiotics including piperacillin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated.
Special Precautions
Bleeding manifestations have occurred in some patients receiving piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken.
As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Leucopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of haematopoietic function should be performed.
For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of piperacillin is advisable to provide guidance for adjusting dosage.
The theoretical sodium content of each 4.5 g vial of TAZPEN is 216 mg sodium (9.39 mmol), which may increase a patient's overall sodium intake. This should be considered when treating patients requiring restricted salt intake. Periodical electrolyte determinations should be made in patients with low potassium reserves and the possibility of hypokalaemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.
Periodical assessment of organ system functions including renal, hepatic and haematopoietic during prolonged therapy is advisable.
Use In Pregnancy & Lactation
Studies in mice and rats have not demonstrated any embryotoxic or teratogenic effects of the piperacillin-tazobactam combination. There are no adequate and well-controlled studies with the piperacillin-tazobactam combination or with piperacillin or tazobactam alone in pregnant women. Piperacillin and tazobactam cross the placenta. Pregnant women should be treated only if the expected benefit outweighs the possible risks to the pregnant woman and fetus.
Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Women who are breastfeeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
Adverse Reactions
Adverse reactions are listed in frequency categories as follows: Very Common ≥10%, Common ≥1%, Uncommon ≥0.1% and <1%, Rare ≥0.01% and <0.1%, Very rare <0.01%.
Infections and infestations: Uncommon: Candidal superinfection.
Blood and lymphatic system: Uncommon: Leukopenia, neutropenia, thrombocytopenia.
Rare: Anemia, bleeding manifestations (including purpura, epistaxis, bleeding time prolonged), eosinophilia, haemolytic anemia.
Very rare: Agranulocytosis, Coombs direct test positive, pancytopenia, prolonged partial thromboplastin time, prothrombin time prolonged, thrombocytosis.
Immune system disorders: Uncommon: Hypersensitivity reaction.
Rare: Anaphylactic/anaphylactoid reaction (including shock).
Metabolism and nutrition disorders: Very rare: Blood albumin decreased, blood glucose decreased, blood total protein decreased, hypokalemia.
Nervous system disorders: Uncommon: Headache, insomnia.
Vascular disorders: Uncommon: Hypotension, phlebitis, thrombophlebitis.
Rare: Flushing.
Gastrointestinal: Common: Diarrhea, nausea, vomiting.
Uncommon: Constipation, dyspepsia, jaundice, stomatitis.
Rare: Abdominal pain, pseudomembranous colitis.
Hepatobiliary: Uncommon: Alanine aminotransferase increased, aspartate aminotransferase increased.
Rare: Bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatitis.
Skin and subcutaneous tissue disorders: Common: Rash.
Uncommon: Pruritis, urticaria.
Rare: Bullous dermatitis, erythema multiforme.
Very Rare: Stevens-Johnson Syndrome, toxic epidermal necrolysis.
Musculoskeletal, connective tissue and bone disorders: Rare: Arthralgia.
Renal and urinary disorders: Uncommon: Blood creatinine increased.
Rare: Interstitial nephritis, renal failure.
Very rare: Blood urea nitrogen increased.
General disorders and administration site conditions: Uncommon: Fever, injection site reaction.
Rare: Rigors.
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Side Effects
Rarely the significant leukopenia may be associated with prolonged therapy. Very rarely, interstitial nephritis may occur. Hepatitis and cholestatic jaundice have been reported with some penicillins and beta-lactamase inhibitors. In common with other beta-lactam antibiotics, hemolytic anemia has been reported rarely with piperacillin and piperacillin/tazobactam. Many of the patients treated in clinical trials were severely ill and had multiple underlying disease and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with piperacillin and tazobactam.
Drug Interactions
Probenecid: Concurrent administration of probenecid and Piperacillin/Tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of neither drug are affected.
Vancomycin: No pharmacokinetic interaction is found between TAZPEN and vancomycin.
Aminoglycosides: No interaction is found between TAZPEN and tobramycin. Whenever TAZPEN is used concurrently with another antibiotic, especially an aminoglycoside, the drug must not be mixed in intravenous solutions or administered concurrently due to physical incompatibility.
The inactivation of aminoglycosides in the presence of penicillin class drugs has been recognised. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. Hence whenever TAZPEN is used concurrently with another antibiotic, especially an aminoglycoside, the drug must not be mixed in IV solutions or administered concurrently due to physical incompatibility.
Heparin: Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system and/or the thrombocyte function.
Vecuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. TAZPEN could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin. Caution is indicated when piperacillin is used perioperatively with vecuronium and similar neuromuscular-blocking agents.
Methotrexate: Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.
Effects on laboratory tests: As with other penicillins, the administration of piperacillin/tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Incompatibilities: Whenever Tazpen is used concurrently with another antibiotic, the drug must be administered separately. The mixing of Tazpen with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
Because of chemical instability, Tazpen should not be used in solutions containing only sodium bicarbonate.
Tazpen should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
Storage
Store below 30°C. Protect from light.
Reconstituted solution should be used immediately. Discard any unused portion after 24 hours if stored at below 25°C, or after 48 hours if stored at refrigerated temperature (2-8°C). Vials should not be frozen after reconstitution.
For further information, please consult the physician or pharmacist.
MIMS Class
ATC Classification
J01CR05 - piperacillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj (white to off-white sterile, lyophilised powder in vial) 4.5 g x 1's, 10's.
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